The technical field of this invention concerns the extrusion of capsules suitable for encapsulation of biologically active factors and other compositions.
There is considerable interest at present in the biologically active products of living cells, including, for example, neurotransmitters, hormones, cytokines, nerve growth factors, angiogenesis factors, blood coagulation factors, lymphokines, enzymes and other therapeutic agents. There is also substantial interest in developing new methods and systems for producing such biological factors, as well as in delivering these factors to subjects for therapeutic purposes.
For example, Parkinson's disease is characterized by the degeneration of the dopaminergic nigrostriatal system. Striatal implantation of polymer rods which release sustained amounts of a neurotransmitter, dopamine, has been reported to alleviate experimental Parkinsonism in rodents, indicating that the release of dopamine alone in the proper target structure may be able to correct this functional deficiency.
Similarly, diabetes is a disease characterized by the degeneration of the pancreatic endocrine system with a resulting loss in the body's ability to produce insulin. Although diabetes can be controlled, to an extent, by daily injections of insulin, optimal treatment protocols must take into account the individual's disease state, as well as changes in a subject's metabolism from day-today. For these reasons, polymeric matrix delivery systems for insulin have not been particularly successful.
Many other diseases are, likewise, characterized by a deficiency in a critical biological factor that cannot easily be supplemented by injections or longer-term, controlled release therapies. Still other diseases while not characterized by substance deficiencies can be treated with biologically active moieties normally made and secreted by cells. Thus, trophic and growth factors may be used to prevent neurodegenerative conditions, such as Huntington's and Alzheimer's diseases.
In contrast to the limited capacity of a polymeric matrix drug release system, the encapsulation of living cells has been proposed as a means to provide a continuous supply of neurotransmitters, hormones and other biological factors. The encapsulation of such cells by a permselective membrane which permits diffusion of the biological factor may not only prohibit the escape of mitotically active cells, but also prevent host rejection in the case of cross species or allogenic transplantation.
A number of researchers have proposed the use of microcapsules, i.e., tiny spheres which encapsulate a microscopic droplet of a cell solution, for both therapeutic implantation purposes and large scale production of biological products. For instance, the microsphere cell capsules disclosed by Sefton et al. Biotechnology and Bioengineering 29:1135-1143 (1987) and Sugamori et al. Trans. Am. Soc. Artf. Intern. Organs 35:791-799 (1989) are produced using a polymer solution to encapsulate a cell suspension in an aqueous culture medium. The polymer solution is delivered through an annulus formed by two concentric needles, while the cell suspension is delivered via the inner needle. The cell suspension and polymer solution form droplets which are blown off the end of the needle by a coaxial air stream. Each droplet falls into a curing bath, in which polymerization of a microcapsule occurs. The morphology sought by Sefton et al. and Sugamori et al. is a microcapsule having an inner sphere of cell solution, concentric with an outer sphere of polymer. This morphology is established during the fall of the droplet from the needle to the curing bath, and is influenced by factors such as the polymer/solvent systems and the relative densities of the polymer solution and cell suspension. The polymer/solvent systems disclosed by Sefton et al. and Sugamori et al. are chosen such that polymer precipitation occurs slowly. In the techniques of Sefton et al. and Sugamori et al. the curing bath serves to extract the polymer solvent. This ensures that polymerization occurs in the bath and not at the extrusion bore. The prior art technique is specifically designed to permit time for the polymer to surround the core material before solidification.
However, there are a number of shortcomings to the microencapsulation approach. For example, the microcapsules can be extremely difficult to handle, including being difficult to retrieve after implantation. The types of encapsulating materials which can be used are constrained by the formation process to polymers which can dissolve in biocompatible solvents. Furthermore, due to the limited diffusional surface area per unit volume of larger size spheres, only a limited amount of tissue can be loaded into a single microcapsule.
An alternative approach has been macroencapsulation, which typically involves loading cells into hollow fibers and then sealing the extremities. In contrast to microcapsules, macrocapsules offer the advantage of easy retrievability, an important feature in therapeutic implants, especially neural implants. However, the construction of macrocapsules in the past has often been tedious and labor intensive. Moreover, due to unreliable closure, conventional methods of macroencapsulation have provided inconsistent results.
In addition, existing techniques often produce macrocapsules with seams. This is due to the fact that an open end of the macrocapsule necessarily results from the macroencapsulation methods. For many applications, it is desirable to have a seamless capsule.
Thus, there exists a need for better techniques for macroencapsulation of cells for both therapeutic implantation and industrial production purposes. Encapsulation techniques which can be practiced in an automated fashion, which permit the usage of a wider range of materials, and which provide more reliable and/or seamless closure would satisfy a long felt need in the art.